Active cancer and ongoing antineoplastic treatments are major factors for severe COVID-19 and death, reasons why the SARS-CoV-2 vaccination remains a priority in cancer patients (CPs). However, ...immunocompromised patients were excluded from major studies on mRNA vaccines, and could have a decreased response to vaccination, as recently demonstrated in solid organ transplant recipients. Herein, we aimed to assess the proportion of antibody response 4 weeks after the first injection of the BNT162b2 (Pfizer-BioNTech) vaccine in CPs and health care workers (HCWs) as the control population.
Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism ...involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.
Genetic landscape of indolent and aggressive Kaposi sarcomas Malouf, G.G.; Lu, X.; Mouawad, R. ...
Journal of the European Academy of Dermatology and Venereology,
December 2022, 2022-Dec, 2022-12-00, 20221201, 2022-12, Volume:
36, Issue:
12
Journal Article
Peer reviewed
Background
Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic ...basis of this difference remains unknown.
Objectives
To explore the tumour mutational burden in indolent and aggressive KS.
Methods
We performed whole‐exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS.
Results
Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy‐number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS.
Conclusions
These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.
Background: Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially colorectal cancer (CRC), and seems to reflect more aggressive histological and clinical ...behaviors. The aim of this study was to evaluate EGFR immunohistochemical reactivity in CRC biopsies, and to analyze its relationship with various histological and clinical characteristics and survival. Patients and methods: A composite EGFR score, obtained by multiplying the grade (% positive cells) by the intensity of labeling (0–9) was used to define patients with low or high EGFR expression whose clinicopathological features were then compared. Univariate tests and multivariate Cox proportional hazards model were applied for data analysis. Results: Tissue sections from 150 CRC patients with a median follow-up of 40 months were examined. Median patient age at diagnosis was 70 years (range 38–89 years). EGFR reactivity was positive for 143 patients (97%) and high for 118 (80%). According to multivariate analysis, EGFR overexpression was significantly associated with tumor stage, with a higher percentage of EGFR overexpression in T3 than T4 (P=0.003) and not with overall survival. Conclusions: EGFR was overexpressed in this CRC patient population and was significantly associated with TNM (tumor–node–metastasis) stage T3. In the context of a new therapeutic strategy using EGFR-targeted therapies, although EGFR remains a controversial prognostic factor, this expression–stage association may play a crucial role in a decision to initiate an adjuvant treatment.
Hypertension (HTN) is one of the most frequent side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. Its incidence and severity are dependent on the type of ...drugs, dose, and schedule used. The recognition of this side-effect is an important issue because poorly controlled HTN could lead to serious cardiovascular events. On another hand, HTN induced by anti-VEGF agents maybe a predictive factor of oncologic response. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians choosing the optimal and least toxic regimen suitable for an individual patient.
A Medline search was carried out using the following criteria: (i) all Medline listings as of 1 January 2000 with abstracts, (ii) English language, and (iii) Humans. The following phrases were used to query the database: (‘hypertension’, OR ‘blood pressure’) AND (‘anti-VEGF’ OR ‘VEGF inhibition’ OR ‘bevacizumab’ OR ‘sunitinib’ OR ‘sorafenib’ OR ‘VEGF Trap’). The references of each article identified were carefully reviewed for additional reference.
Lifestyle modification should be encouraged. However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention. Only one randomized study showed a beneficial effect of a calcium channel blocker use to prevent or minimize HTN secondary to antiangiogenic therapy. Nitrates looks as effective in controlling such side-effect.
No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Blood pressure-lowering drugs should be individualized to the patient's clinical circumstances and angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.
Metastatic colorectal cancer is a particularly frequent and severe cancer. Patients die mainly from metastatic disease; however, the survival of these patients has dramatically improved with the ...progress in chemotherapeutic regimens as new routes of administration and introduction of more potent cytotoxic agents administered in sequential 5-FU-folinic acid-irinotecan/5-FU-folinic acid-oxaliplatine strategies. Biologic therapies have been also developed targeting two different pathways, angiogenesis and the epidermal growth factor receptor. Their combination with chemotherapy leads to improved progression-free survival and overall survival in some cases as the addition of cetuximab in wild-type K-Ras tumors. The objectives of this expert conference were to review the different options, the available prognostic or predictive factors to optimally guide the treatment.
Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. ...EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations but its prognostic value in colorectal cancer progression remains unclear. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation. This review focuses on the potential role of EGFR signaling in the survival of colorectal tumor cells and the possible modulation of such signaling pathways by EGFR inhibitors so as to increase tumor control or render tumor cells more sensitive to conventional therapy.
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